This study seeks to estimate the effectiveness of newly FDA-approved extended-release naltrexone (XR-NTX) for opioid relapse prevention among opioid dependent participants leaving a large urban jail. While methadone treatment is available in NYC jails, many heroin and other opioid users, including HIV and Hepatitis C (HCV) infected individuals, decline this treatment at arrest, and instead leave jail out-of-treatment and at extraordinarily high risk for immediate opioid relapse, fatal overdose, and HIV/HCV-related adverse outcomes, including resuming patterns of injection drug use and unsafe sex. XR-NTX, an injectable non-narcotic opioid antagonist with no abuse potential, which blocks the usual physiologic effects of heroin and other opioids for up to 4 weeks, constitutes a new pharmacotherapy option for individuals not opting for agonist medications. We propose a randomized trial of XR-NTX versus enhanced treatment-as-usual to establish XR-NTXs effectiveness as re-entry opioid relapse and HIV/HCV risk prevention. Further, an important question is how XR-NTX compares to methadone maintenance standard-of-care, and this study will recruit an additional, non-randomized, quasi-experimental methadone cohort for comparative effectiveness purposes.